The HLA‐DRB, ‐DQB polymorphism and anti‐insulin antibody response in Slovenian patients with type 1 diabetes

Abstract

A combination of specific HLA class II antigens and the presence of type 1 diabetes (T1D)-related antibodies has a high positive predictive value for T1D but low sensitivity. The aim of the present study was to determine the frequencies of HLA-DRB-DQB deduced haplotypes associated with susceptibility and protection in Slovenian patients with established T1D, to evaluate the relationship between the HLA-DRB1-QBP-DQB1 haplotypes and the presence of insulin autoantibodies (IAA) and glutamic acid decarboxylase antibodies (GADA), and to access the possible impact of polymorphic QBP promoters on this relationship. A cohort of 135 patients with T1D (age 17.5 +/- 7.0 years, duration of T1D 9.14 +/- 6.3 years) was investigated. HLA-DRB1 and DQB1 alleles were typed using the polymerase chain reaction (PCR)-reverse line blot method. QBP promoter region alleles were determined using PCR-sequence-specific oligonucleotide hybridization (SSO) and PCR-sequence-specific primers (SSP). IAA and GADA antibodies were determined by enzyme-linked immunosorbent assay (ELISA). The chi-square test with Yates' correction was used for statistical analysis. Deduced haplotypes DRB1*0301-DQB1*0201 (P = 0.0001, OR = 3.4), DRB1*0401-DQB1*0302 (P = 0.0001, OR = 29.8), and DRB1*0402-DQB1*0302 (P = 0.008, OR = 4.7) were significantly more common, and DRB1*1501-DQB1*0602 (P = 0.0001, OR = 0.03) significantly less common in the investigated cohort than in a Slovenian control group. The highest risk and the strongest protective HLA-DR-DQ haplotypes found in Slovenian patients with T1D did not differ from those found in other Caucasian populations. While the DRB1*0301-QBP2.1-DQB1*0201 haplotype, where QBP2.1 did not help to further distinguish DQB1*0201-possessing haplotypes in IAA-positive and IAA-negative patients, was strongly associated with the presence of IAA, the DRB1*0101-QBP5.12-DQB1*0501 haplotype, although not protective compared to the control population, was associated with an absence of IAA in the investigated cohort. It is suggested that there may be a combined influence of the QBP5.12 promoter and the DQB1*0501 functional molecule on reduced IAA production.

Genetic risk for co‐occurrence of type 1 diabetes and celiac disease is modified byHLA‐C and killer immunoglobulin‐like receptors

“…In number of previous studies, C*07 was often found in combination with B*07 and DRB1*15:01 , forming second most common haplotype in many Caucasian populations. It was shown that DRB1*15:01‐DQB1*06:02 conferred protection against T1D . Interestingly, in this study, this protective effect could not be proven to extend to C*07 .…”

“…While DQ8 conveys higher risk for T1D than DQ2 (9) in CD approximately 90% of the patients carry the DQ2 (10). DQ8 was also a predominant risk factor in Slovenian patients with T1D (11) and DQ2 in patients with CD (12).…”

An influence of HLA-A, B, DR, DQ, and MICA on the occurrence of Celiac disease in patients with type 1 diabetes

“…A group of 37 individuals with T1D and CD, diagnosed according to the revised European Society of Pediatric Gastroenterology and Nutrition (ESPGAN) criteria with histological conformation (29), was compared with a well‐defined group of 67 individuals with only T1D, previously typed for HLA‐DRB1 and DQB1 (30). All 37 individuals with T1D and CD were diagnosed with CD after the onset of T1D.…”

HLA class II susceptibility pattern for type 1 diabetes (T1D) in an Iranian population

“…On the other hand, some haplotypes, such as HLA‐DR2 (DRB1*15:01 – DQA1*01:02 – DQB1*06:02), which is also the most common DR–DQ haplotype in Caucasians, strongly contribute to protection from T1D in a dominant manner over susceptibility haplotypes (Ettinger et al ., , ; Cerná, ; Noble & Valdes, ; Noble & Erlich, ). A limited number of studies in Iranian population indicate that the prevalence of risk‐associated and/or protective HLA alleles for T1D (Sayad et al ., ; Rabbani et al ., ) is almost in line with various reports from other Caucasians (Noble et al ., ; Saruhan‐Direskeneli et al ., ; Petrone et al ., , ; Battelino et al ., ; Hermann et al ., ; Erlich et al ., ; Ilonen et al ., ; Cifuentes et al ., ). Notably, observation of few differences between results of those limited studies in Iranian population and other Caucasians or even some Asian population is reasonable due to several contributing factors including ethnic origin of subjects in each study, sample size, different incidence of T1D in each region and other unknown factors (Park et al ., ; Park & Eisenbarth, ; Park, , ; Polychronakos & Li, ).…”